title: In vitro phenotypic characterization of hepatitis C virus NS3 protease variants observed in clinical studies of telaprevir.
abstract: Telaprevir is a linear, peptidomimetic small molecule that inhibits hepatitis C virus (HCV) replication by specifically inhibiting the NS3·4A protease. In phase 3 clinical studies, telaprevir in combination with peginterferon and ribavirin (PR) significantly improved sustained virologic response (SVR) rates in genotype 1 chronic HCV-infected patients compared with PR alone. In patients who do not achieve SVR after treatment with telaprevir-based regimens, variants with mutations in the NS3·4A protease region have been observed. Such variants can contribute to drug resistance and limit the efficacy of treatment. To gain a better understanding of the viral resistance profile, we conducted phenotypic characterization of the variants using HCV replicons carrying site-directed mutations. The most frequently observed (significantly enriched) telaprevir-resistant variants, V36A/M, T54A/S, R155K/T, and A156S, conferred lower-level resistance (3- to 25-fold), whereas A156T and V36M+R155K conferred higher-level resistance (>25-fold) to telaprevir. Rarely observed (not significantly enriched) variants included V36I/L and I132V, which did not confer resistance to telaprevir; V36C/G, R155G/I/M/S, V36A+T54A, V36L+R155K, T54S+R155K, and R155T+D168N, which conferred lower-level resistance to telaprevir; and A156F/N/V, V36A+R155K/T, V36M+R155T, V36A/M+A156T, T54A+A156S, T54S+A156S/T, and V36M+T54S+R155K, which conferred higher-level resistance to telaprevir. All telaprevir-resistant variants remained fully sensitive to alpha interferon, ribavirin, and HCV NS5B nucleoside and nonnucleoside polymerase inhibitors. In general, the replication capacity of telaprevir-resistant variants was lower than that of the wild-type replicon.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ardzinski
authors.forename: Michelle
authors.initials: M
authors.lastname: Nelson
authors.forename: Dugan
authors.initials: D
authors.lastname: Reagan
authors.forename: Doug
authors.initials: D
authors.lastname: Bartels
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Olivier
authors.initials: O
authors.lastname: Nicolas
authors.forename: B Govinda
authors.initials: BG
authors.lastname: Rao
authors.forename: Ute
authors.initials: U
authors.lastname: Müh
authors.forename: Brian
authors.initials: B
authors.lastname: Hanzelka
authors.forename: Ann
authors.initials: A
authors.lastname: Tigges
authors.forename: Rene
authors.initials: R
authors.lastname: Rijnbrand
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir